CA2099870A1 - 1-aryl-4-piperazinylcyclohexanecarbonitriles, the preparation and use thereof - Google Patents
1-aryl-4-piperazinylcyclohexanecarbonitriles, the preparation and use thereofInfo
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- CA2099870A1 CA2099870A1 CA002099870A CA2099870A CA2099870A1 CA 2099870 A1 CA2099870 A1 CA 2099870A1 CA 002099870 A CA002099870 A CA 002099870A CA 2099870 A CA2099870 A CA 2099870A CA 2099870 A1 CA2099870 A1 CA 2099870A1
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- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
- C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
- C07D295/182—Radicals derived from carboxylic acids
- C07D295/185—Radicals derived from carboxylic acids from aliphatic carboxylic acids
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- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/57—Nitriles
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- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D295/155—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
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- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
- C07D333/24—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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Abstract
Compounds have formula (I), in which Ar, R1, R2, P and Q have the meanings given in the description. Also disclosed is their production. These compounds are useful for therapeutical purposes.
Description
. 2 ~ 9 ~ ~ 7 o. Z . 0050/42305 Novel l-ary1-4-~iPerazinylc~clohexanecarbonitrile~, the preparation and use thereof The present invention relates to 1-aryl-4-pipera-zinylcyclohexanecarbonitrile~, to pr.ocesses for the preparation thereof and to the use thereof a~ drugs.
Derivatives of 4-amino-1-phenylcyclohexane-carbonitrile have been disclosed. ThuR, ZA-C 66/5399 discloses compound~ with morpholine- and mescaline-antagonistic propertie3, and DE-B 17 93 383 disclo~es compound~ with spasmolytic, hypotensive and neuroleptic properties. 4-Piperidinyl-l-phenylcyclohexane-carbonitrile~ with a strong antihistamine action have been described in EP-A 34 415.
In addition, a large number of qubstituted piper-azines with antiarrhythmic or blood~low-promoting properties has been diqclosed. ~hese are predominantly benzhydryl- or diarylbutylpiperazine~, of which flunarizine i9 the best known compound. It is used for the therapy of disturbances of peripheral and cerebral blood flow tDE-A 19 29 330, DE-A 33 26 148, DE-A 25 47 570, EP-A 256 890, DE-A 36 00 390, EP-A 159 56S, EP-A 285 219).
We have now found that l-aryl-4-piperazinylcyclo-hexanecarbonitriles of the formula I
-~ ~c N N - P - Q
where Ar i3 phenyl which i8 unsubstituted or mono~ubstituted by chlorine, methyl, methoxy or trifluoromethyl or mono- or di~ubstituted by fluorine, or is 2- or 303-thienyl or 2-, 3- or 4-pyridyl, Rl i~ hydrogen, fluorine, chlorine, trifluoromethyl, methoxy, methyl, nitro, cyano, acetyl, methoxycar-bonyl or ethoxycarbonyl, R2 is hydrogen, chlorine or methyl, ~ , . . ''-' , .
. .
. ~ .. .
Derivatives of 4-amino-1-phenylcyclohexane-carbonitrile have been disclosed. ThuR, ZA-C 66/5399 discloses compound~ with morpholine- and mescaline-antagonistic propertie3, and DE-B 17 93 383 disclo~es compound~ with spasmolytic, hypotensive and neuroleptic properties. 4-Piperidinyl-l-phenylcyclohexane-carbonitrile~ with a strong antihistamine action have been described in EP-A 34 415.
In addition, a large number of qubstituted piper-azines with antiarrhythmic or blood~low-promoting properties has been diqclosed. ~hese are predominantly benzhydryl- or diarylbutylpiperazine~, of which flunarizine i9 the best known compound. It is used for the therapy of disturbances of peripheral and cerebral blood flow tDE-A 19 29 330, DE-A 33 26 148, DE-A 25 47 570, EP-A 256 890, DE-A 36 00 390, EP-A 159 56S, EP-A 285 219).
We have now found that l-aryl-4-piperazinylcyclo-hexanecarbonitriles of the formula I
-~ ~c N N - P - Q
where Ar i3 phenyl which i8 unsubstituted or mono~ubstituted by chlorine, methyl, methoxy or trifluoromethyl or mono- or di~ubstituted by fluorine, or is 2- or 303-thienyl or 2-, 3- or 4-pyridyl, Rl i~ hydrogen, fluorine, chlorine, trifluoromethyl, methoxy, methyl, nitro, cyano, acetyl, methoxycar-bonyl or ethoxycarbonyl, R2 is hydrogen, chlorine or methyl, ~ , . . ''-' , .
. .
. ~ .. .
-2~ ~ 9 ~ 7 ~ o.z . 0050/42305 P iR straight-chain or branched alkylene of from 2 to 8 carbon~, which can be monosu~tituted by oxo, hy-droxyl, methoxy or acetoxy, and Q is oxygen or ~ulfur, N~ or a bond, and the alt~ thereof with physiologically tolerated acids, have an outstanding antihypoxic and antiischemic action.
Suitable physiologically tolexated acids are inorganic acid~ such as hydrochloric acid, Rulfuric acid, phosphoric acid, nitric acid or or~anic acids such as tartaric acid, lactic acid, malic acid, citric acid, maleic acid, fumaric acid, oxalic acid, acetic acid, gluconic acid, mucic acid or methanesulfonic acid.
In formula I, Ar i~ preferably phenyl which i~
unsubstituted or monosubstituted by fluorine or chlorine, R1 is preferably hydrogen, fluorine or chlorine or meth-oxy, and P-Q i~, in particular, alkyleneoxy or alkylene-thio o~ 2 or 3 carbon~, or 2-hydroxypropyleneoxy. Rl and R2 can be in positions 2, 3 or 4 on the phenyl ring.
If P contains hydroxyl, for example, the com-pounds of the formula I have a center of chirality~ They therefore exi~t in the form of optical antipodes (ena-ntiomers). These can be obtained by conventional method~, by salt formation with chiral auxiliarie~ such as tar-taric acid, dibenzoyltartaric acid or mandelic acid and fractional crystallization followad by liberation of the ba~es from the salts, or else by synthesis from 3uitable chiral precursors.
Furthermore, becau~e o~ the cyclohexane ring, the compounds may al~o occur as ci~ and trans isomers. ~hese geometrical isomers can be obtained in a conventiona}
manner by separation proce~ses such as cry~tallization or chromatography at the final stage or at an earlier ~tage, or al~e by carrying out ~uitable reaction~.
The present invention al30 relat~s to proces es for preparing the compound3 of the formula I, which compri~e either .
' 2 0 9 9 .~ 7 ~
Suitable physiologically tolexated acids are inorganic acid~ such as hydrochloric acid, Rulfuric acid, phosphoric acid, nitric acid or or~anic acids such as tartaric acid, lactic acid, malic acid, citric acid, maleic acid, fumaric acid, oxalic acid, acetic acid, gluconic acid, mucic acid or methanesulfonic acid.
In formula I, Ar i~ preferably phenyl which i~
unsubstituted or monosubstituted by fluorine or chlorine, R1 is preferably hydrogen, fluorine or chlorine or meth-oxy, and P-Q i~, in particular, alkyleneoxy or alkylene-thio o~ 2 or 3 carbon~, or 2-hydroxypropyleneoxy. Rl and R2 can be in positions 2, 3 or 4 on the phenyl ring.
If P contains hydroxyl, for example, the com-pounds of the formula I have a center of chirality~ They therefore exi~t in the form of optical antipodes (ena-ntiomers). These can be obtained by conventional method~, by salt formation with chiral auxiliarie~ such as tar-taric acid, dibenzoyltartaric acid or mandelic acid and fractional crystallization followad by liberation of the ba~es from the salts, or else by synthesis from 3uitable chiral precursors.
Furthermore, becau~e o~ the cyclohexane ring, the compounds may al~o occur as ci~ and trans isomers. ~hese geometrical isomers can be obtained in a conventiona}
manner by separation proce~ses such as cry~tallization or chromatography at the final stage or at an earlier ~tage, or al~e by carrying out ~uitable reaction~.
The present invention al30 relat~s to proces es for preparing the compound3 of the formula I, which compri~e either .
' 2 0 9 9 .~ 7 ~
- 3 - O.z. 0050/42305 a) reacting a compound of the formula II
II
~ro NC
where Ar ha the stated meaning~, with a piperazine derivative III
~N N--P--Q~
~ III
where P, Q, R1 and R~ have the ~tated meanings, or b~ reacting a compound of the ormula IV
Ar IV
A~ N NEI
~C
where Ar again has the abovementioned meaning~, with a compound of the formula V
X-~--Q~ V
Rl-where P, Rl and R2 [~ic] have the abovementioned meanings, and X i8 a reactive acid re~idue, or c) if P i~ monosub~tituted by hydroxyl, and Q is not N~, reacting a compound of the formula IV with a compound of the formula VI
R3 ~2 ~L (ca2)"--Q~ VI
where Q, R~ and ~Z have th0 abovementioned meanings, R3 i~ C1~-alkyl, and n i~ 1 or 2, and ~ub~equently converting the re~ulting compound~ where appropriate with phy~iologically tolerated acid~ into ` ' . ~ . '.~' ' , ' -, :
2~9~
, - 4 - O.Z. 0050/42305 their 8alt8.
The known reductive amination of compounds of the formula II with piperazine~ of the formula III can be carried out with reducing agents such a~ cata}ytically 5activated hydrogen, in which ca e a noble metal catalyst ~uch a~ palladium on carbon i5 preferably used, with complex metal hydride~ such a~ sodium cyanoborohydride or else with for~ic acid in a suitable solvent at, prefer~
ably, from 0 to 100C. Suitable solvents are aceto-10nitrile, dimethylformamide, tetrahydrofuran, toluene or lower alcohols such as methanol or ethanol.
Depending on the reducing agent and the condi-tions used, either mixtures of the cis and trans isomers or the sub~tantially pure, more stable cis isomer are obtained.
Process b) is preferably carried out in polar organic solvents such as alcohols (eg. methanol, ethanol, isopropanol), a lower ketone (pre~erably acetone, methyl ethyl ketone or methyl isobutyl ketone), in dimethyl-20formamide, dimethyl sulfoxide, acetonitrile or, where appropriate, al~o in a hydrocarbon such as toluene, advantageously in the presence of a base to trap the acid which is formed (~uch as sodium carbonate, potassium carbonate, calcium carbonate, triethylamine or pyridine) 25at elevated temperature, preferabiy at from 20 to 120C.
Suitable reactive acid residues X are chlorine, bromine or iodine atoms and sulfonate group~, preferably methane-sulfonyl, benzenesulfonyl, p-toluenesulfonyl or tri-fluoromethanesulfonyl.
30The conventional reaction of epoxides of the formula VI with the piperazine~ of the formula IV i9 expediently carried out in a solvent such as aceto-nitril~; dim~thylformamide, tetrahydrofuran or a lower alcohol (preferably methanol or ethanol) at elevated 35temperature~ (from 30 to 120C), preferably at boiling points ~sic~ of the ~olvent. If optically active epoxides are employed, the compounds accordi~g to the invention 7 ~
II
~ro NC
where Ar ha the stated meaning~, with a piperazine derivative III
~N N--P--Q~
~ III
where P, Q, R1 and R~ have the ~tated meanings, or b~ reacting a compound of the ormula IV
Ar IV
A~ N NEI
~C
where Ar again has the abovementioned meaning~, with a compound of the formula V
X-~--Q~ V
Rl-where P, Rl and R2 [~ic] have the abovementioned meanings, and X i8 a reactive acid re~idue, or c) if P i~ monosub~tituted by hydroxyl, and Q is not N~, reacting a compound of the formula IV with a compound of the formula VI
R3 ~2 ~L (ca2)"--Q~ VI
where Q, R~ and ~Z have th0 abovementioned meanings, R3 i~ C1~-alkyl, and n i~ 1 or 2, and ~ub~equently converting the re~ulting compound~ where appropriate with phy~iologically tolerated acid~ into ` ' . ~ . '.~' ' , ' -, :
2~9~
, - 4 - O.Z. 0050/42305 their 8alt8.
The known reductive amination of compounds of the formula II with piperazine~ of the formula III can be carried out with reducing agents such a~ cata}ytically 5activated hydrogen, in which ca e a noble metal catalyst ~uch a~ palladium on carbon i5 preferably used, with complex metal hydride~ such a~ sodium cyanoborohydride or else with for~ic acid in a suitable solvent at, prefer~
ably, from 0 to 100C. Suitable solvents are aceto-10nitrile, dimethylformamide, tetrahydrofuran, toluene or lower alcohols such as methanol or ethanol.
Depending on the reducing agent and the condi-tions used, either mixtures of the cis and trans isomers or the sub~tantially pure, more stable cis isomer are obtained.
Process b) is preferably carried out in polar organic solvents such as alcohols (eg. methanol, ethanol, isopropanol), a lower ketone (pre~erably acetone, methyl ethyl ketone or methyl isobutyl ketone), in dimethyl-20formamide, dimethyl sulfoxide, acetonitrile or, where appropriate, al~o in a hydrocarbon such as toluene, advantageously in the presence of a base to trap the acid which is formed (~uch as sodium carbonate, potassium carbonate, calcium carbonate, triethylamine or pyridine) 25at elevated temperature, preferabiy at from 20 to 120C.
Suitable reactive acid residues X are chlorine, bromine or iodine atoms and sulfonate group~, preferably methane-sulfonyl, benzenesulfonyl, p-toluenesulfonyl or tri-fluoromethanesulfonyl.
30The conventional reaction of epoxides of the formula VI with the piperazine~ of the formula IV i9 expediently carried out in a solvent such as aceto-nitril~; dim~thylformamide, tetrahydrofuran or a lower alcohol (preferably methanol or ethanol) at elevated 35temperature~ (from 30 to 120C), preferably at boiling points ~sic~ of the ~olvent. If optically active epoxides are employed, the compounds accordi~g to the invention 7 ~
- 5 - O.Z. 0050/42305 are obtained as pure enantiomer~.
The starting compound~ of the formulae II to VI
are di~clo~ed in the literature or can be prepared in a conventional mannerO
The compounds according to the invention are suitable for treating acute and chronic degenerative processe~ of the central nervou~ system and other organ~.
These include, in particular, di~orders attributable to an acute or chronic disturbance of the blood sspply or o~
cellular metabolism, such as ischemic cerebral insult~, cerebral hemorrhage-q, vascular encephalopathie3 ancl the dementias resulting therefrom, hypoglycemia3, epilep~ie~, migraine, traumatic le~ions of the brain and of the spinal cord, and ischemia-related degeneration of the heart, of the kidneys and of okher organs, especially in connection with transplants and other surgical interven-tions.
The cerebroprotective action of the novel com-pounds was estimated on the normobaric hypoxic hypoxia o~
mice and on the global cerebral ischemia of mice (methods in: H.P. Hofmann et al., Arzneim.-Forsch./Drug Re~. 39, 1989, 304 - 308). The novel sub~tances proved in both models to have pronounced protective activity, which was evident from the great increa~e ln the ~urvival time of substance-treated animals compared with placebo-treated control animals.
Likewise, the neuroprotective action of the novel substances was demon~trated in the model o temporary forebrain ischemia in the Mongolian gerbil ~method in:
L.Szabo and H.P.~ofmann, Arzne~m.-Forsch./Drug Re~.39, 1989, 314-319). In placebo-treated control animal~, the brief interruption of the blood ~upply lead~ to the death of i~chem1a-~ensitive nerve cells in the hippocampus.
Treatment with the novel compou~ds distinctly reduceY the extent of neurenal damage~ which represent~ a relevant parameter for the antiischemic activity of the novel ~ub~tances.
;: . - .
' `: `~' ~' ' , , ` , ;
.
. .
.
2 0 ~J ~
The starting compound~ of the formulae II to VI
are di~clo~ed in the literature or can be prepared in a conventional mannerO
The compounds according to the invention are suitable for treating acute and chronic degenerative processe~ of the central nervou~ system and other organ~.
These include, in particular, di~orders attributable to an acute or chronic disturbance of the blood sspply or o~
cellular metabolism, such as ischemic cerebral insult~, cerebral hemorrhage-q, vascular encephalopathie3 ancl the dementias resulting therefrom, hypoglycemia3, epilep~ie~, migraine, traumatic le~ions of the brain and of the spinal cord, and ischemia-related degeneration of the heart, of the kidneys and of okher organs, especially in connection with transplants and other surgical interven-tions.
The cerebroprotective action of the novel com-pounds was estimated on the normobaric hypoxic hypoxia o~
mice and on the global cerebral ischemia of mice (methods in: H.P. Hofmann et al., Arzneim.-Forsch./Drug Re~. 39, 1989, 304 - 308). The novel sub~tances proved in both models to have pronounced protective activity, which was evident from the great increa~e ln the ~urvival time of substance-treated animals compared with placebo-treated control animals.
Likewise, the neuroprotective action of the novel substances was demon~trated in the model o temporary forebrain ischemia in the Mongolian gerbil ~method in:
L.Szabo and H.P.~ofmann, Arzne~m.-Forsch./Drug Re~.39, 1989, 314-319). In placebo-treated control animal~, the brief interruption of the blood ~upply lead~ to the death of i~chem1a-~ensitive nerve cells in the hippocampus.
Treatment with the novel compou~ds distinctly reduceY the extent of neurenal damage~ which represent~ a relevant parameter for the antiischemic activity of the novel ~ub~tances.
;: . - .
' `: `~' ~' ' , , ` , ;
.
. .
.
2 0 ~J ~
- 6 - O.Z. 00~0/42305 ~he compound~ according to the invention can be aclministered orally, rectally or parenterally (sub-cutaneou~ly, intravenously, intramu~cularly, tran~-dermally) in a conventional manner.
The dosage depends on the age, condition and weight of the patient and on the mode of administration.
As a rule, the daily do~e of active substance i3 from about 0.1 to 20 mg/kg of body weight on oral admini~tr-ation and from about 0.01 to 2 mg/kg of body weight on parenteral administration. Satisfactory re~ult~ are normally achieved with daily oral do~es of from 10 to 100 mg and parenteral dose~ of from 1 to 10 mg.
The novel compounds can be admini~tered in the conventional -~olid or liquid pharmaceutical forms, eg.
uncoated or (film-)coated tablet~, capsules, powders, granules, suppositorie~, solution~, ointments, creams, sprays or transdermal therapeutic sy~tem~. The~e are prepared in a conventional manner in which the active substances can be proces~ed with the conventional pharma-ceutical auxiliaries such as tablet binders, filler~, preservatives, tablet disintegrants, flow regulators antioxidants and/or propellant gases (cf. H. Sucker et al., Pharmazeutische Technologie, ~hieme-Verlag, Stuttgart, 1978). The pharmaceutical forms obtained in thi~ way normally contain ~rom 1 to 75~ by weight of the active substance.
EXAMPLES
A. Preparation of the starting compounds a) 4-(4-benzylpiperazinyl)1-phenylcyclohexanecar-bonitrile 35.0 g of 4-cyano-4-phenylcyclohexanone (0.176 mol), tprepared a~ di~clo~ed in J. Amer.
Chem. Soc. 74, (1972~ 773) were dissolved with 31 g of l-benzylpiperazine (0.176 mol) and 21 g of acetic acid i~ 200 ml of ethanol and, at room temperature, a solution of 12.5 g of sodium cyano-borohydride ~0.19 mol) was slowly added dropwise.
,: , .: ' . ' -- - 2 Q 9~ ~ ~ O o. z . OOS0/42305 The mixture wa~ stirred ov~rnight, and then water was added and the mixture was extracted with dichloromethane. Drying and r~moval of the solvent by distillation resulted in a residue of 46.6 g (76%) of oil.
The dihydrochloride wa~ obtained by treat-ment with hydrochloric acid in isopropanol, C24H29N3 x 2 ~Cl, melting point c 3004C.
Thin-layer chromatography and NMR of thi~
product showed that it was composed of roughly equal amounts of the cis and trans isomers.
b) cis-4-(4-benzylpiperazinyl~l-phenylcyclohexane-carb~nitrile The isomer mixture from a) was dis~olved in ethyl acetate, and hexane was added to opalescence.
The pure cia compound crystallized out overnight.
Filtration with suction resulted in 15.5 g (33~).C24H~9N3, melting point 120-123~C.
c) cis-4-~4-benzylpiperazinyl)1-phenylcyclo-hexanecarbonitrile 5 g o~ 4-cyano-4-phenylcyclohexanone (0.025 mol) were heated with 4.4 g (0.025 mol) of l-benzylpiperazine to 100C and then 1.5 ml of formlc acid were qlowly added dropwise while stirring, and the mixture was stirred at 100C for a further 3 h. After cooling, 10 ml of ethyl acetate/hexane mixture were added: after leaving to stand overnight, 5.0 g (55%) of pure compound were obtained. C2~2aN3, melting point 120-123C.
d) 4-piperazinyl-1-phenylcyclohexanecarbonitrile 12.7 g (0.035 mol) of the product prepared as in a) were hydrogenated with 1 g of 10% Pd on carbon catalyst and hydrogen in methanolic hydro-chloric acid ~olution under atmo~pheric pressure.
After hydrogen uptake ceased, the catalyst wa~
filtered off and the ~olution was evaporated. After treatment with alkali and extraction with ether, .
.
~ ~ . , ' ,' ' , :, :. ~ . ,; .~. . .. ..
~ s~ a o.æ. 0050/42305 the above base was i301ated a~ ci~/tran~ i~omer mixture.
Cl7~23N3, yield 95%, C17H23N3 x 2 HCl dihydrochloride, melting point > 330C
e) cis-4-piperazinyl-1-phenylcyclohexanecarbonitrile The compound wa~ obtained from the product obtained as in b) by hydrogenation in a simllar manner to d). Yield Cl,H23N~, melting point 109-113C
~) Preparation of the compounds according to the inven-}0 tion Proce~s a.
cis-(4-Cinnamyl)piperazinyl-l-phenylcyclo-hexanecarbonitrile 6.0 g ~0.03 mol of 4-cyano-4-phenylcyclohexanone were heated with 6.1 g ~0.03 mol~ o~ cinnamylpiperazine to 100C and then 1.5 g (0.033 mol) o~ ~ormic acid were ~lowly added dropwise, while ~tirring, and the mixture wa~ ~tirred at 100C for a further 3 h.
It was the~ diluted with ethyl acetate and wa~hed with 2 N sodium hydroxide ~olution. The organic phaYe was dried and evaporated. The re~idue was taken up in i~opropanol and the hydrochloride was obtained by addition of i~opropa~olic hydrochloric acid. Yield: 50%
C25~31N3 x 2 ~Cl dihydrochloride, melting point > 250C
The following were prepared in a ~imilar manner:
cis-4-~4-~3-(4-Fluorophenoxy) 2-hydroxypropyl]pipera zinyl}l-(4-fluorophenyl)cyclohexanecarbonitril~
C2~H4lF2N3 x 2 HCl dihydrochlorids, melting point > 250C.
EXAMPL~ 3 ci~-4-{4-~3-(4-Fluorophenoxy~-2-hydroxypropyl]pipera zinyl}l-~2-chlorophe~yl)cyclohexanec~rbonitrile C26~3~ClFN3O2 x 2 ~Cl dihydrochloride, m~lting point > 250C.
.
'`` : .: ' `
209~
_ g _ o.z~ 0050/42305 cis-4-~4-[3-Phenoxy-2 hydroxypropyl]piperazinyl}l-~3-methoxyphenyl)cyclohexanecarbonitrile C27H35N3O3 x 2 HCl dihydrochloride, melti.ng point > 290C.
EXA~PLE 5 cis-4-[4-(3-Phenoxy-2-hydroxypropyl)piperazinyl}1-phenyl-cyclohexanecarbonitrile C26H33N3O2 x 2 HCl dihydrochloride, melti.ng point ~ 250C.
ci~-4-{4-[3-(4-Fluorophenoxy)-2-hydroxypropyl]pipera-zinyl}1-(2-pyridyl)cyclohexanecarbonitrile C2sH3lFN402 x 2 HCl dihydrochloride, melting point 274-278C.
EXAMPL~ 7 ciY-4-{4-[2-(4-Fluorophenoxy)ethyl]piperazinyl~1-(2-pyridyl)cyclohexanecarbonitrile C24H29FN40 x 2 HCl dihydrochloride, me~ting point 282-287C.
E%AMPLE 8 cis-4-{4-[3-(4-Fluorophenoxy)-2-hydroxypropyl]pipera-zinyl}l-(2-thienyl)cyclohexanecarbonitrile Cz4H30FN3O2S x 2 HC1 dihydrochloride, melting point > 250C.
ci~-4-{4-~2-(4-Fluorophenoxy)ethyl]piperazinyl}1-(4-chlorophenyl)cyclohexanecarbonitrile C25~29ClFN30 x 2 HC1 dihydrochloride, melting point 2io-2800c.
cis-4-{4-~3-(4-Fluorophenoxy)-2-hydroxypropyl~pipera-zinyl}l-(3-methoxyphenyl)cyclohexanecarbonitrile C27H34FN3O3 x 2 HC1 dihydrochloride, melting point 29~-300C.
EXAMPL~ 11 cis-4-~4-t3-~4-Fluorophenoxy)-2-hydroxypropyl]pipera-zinyl}l-(3-chlorophenyl)cyclohexanecarbonitrile C26H3~ClFN3O2 x ~ HCl dihydrochloride, melting point 250C.
: .
' . ~
, ~- 2Q~S3~
- 10 - O.Z. 0050/42305 cis-4-{4-~3-(4-Fluorophenoxy~-2-hydroxypropyl]pipera-zinyl}l-(4-methoxyphenyl)cyclohexanecarbonitrile C2,H34FN3O3 x 2 HCl dihydroc~loride, melting point ~ 280C
ci~-4-{4-[3-(4-Fluorophenoxy)-2-hydroxypropyl]pipera-zinyl}l-(2-methoxyphenyl)cyclohexanecarbonitrile C27H34FN3O3 x 2 HCl dihydrochloride, melting point ~ 250C.
EXAMPL~ 14 cis-4-{4-[3-(4 F}uorophenoxy)-2-hydroxypropyl]piper-azinyl}l-(4-hydroxyphenyl)cyclohexanecarbonitrile C28~32FN303 x 2 HCl dihydrochloride, melting point > 250C.
EXA~PLE 15 4-t4-(3-Phenoxypropyl]piperazinyl-l-phenylcyclohexane-carbonitrile [ 9iC ]
5-0 g (0-025 mol) of 4-cyano-4-phenylcyclohexa-none and 5.5 g ~0.025 mol) of 3-phenoxypropylpiperazine were dis~olved with 3.0 g o acetic acid in 70 ml of ethanol and then, while stirring at room temperature, a solution of 1.7 g (0.027 mol) of sodium cyanoborohydride was slowly added dropwise. The mixture was stirred ovsrnight and then diluted with water and extracted with dichloromethane. The organic pha3e was ~ubsequently washed wi~h dilute acid (p~ 4), dilute qodium hydroxide solution and water and finally dried and evaporated. The residue was converted into the hydrochloride with i90-propanolic hydrochloric acid, and the product was recry~talllzed from isopropanol/watsr.
Yield: 50%, Cz~33NsO x 2 ~Cl dihydrochloride, melting point > 250C
The following compound~ were prepared in a sLmilar manner:
EXAMPL~ 16 4~{4-t3-(4-Fluorophenoxy)-2-hydroxypropyl]piperazlnyl}-1-t2-methylphenyl)cyclohexanecarbonitrile C27H34FN3Oz x 2 HCl dihydrochloride, melting point ~ 250C.
2~9~7~
U. Z . 0050/~1s2305 4-{4-~2-(4-Chlorothiophenoxy)ethyl]piperazinyl~1-phenyl-cyclohexanecar~onitrile [~ic]
C25H30ClN3S x 2 ~Cl dihydrochloride, melting point > 270C.
4-~4-[3-(4-Fluorophenoxy)propyl]piperazinyl}l-phenyl-cyclohexanecarbonitrile C26H32FN30 x 2 HCl dihydrochloride, melting point > 250C.
The cis/trans i~omer~ of the compound were separated by preparative column chromatography.
Sorbent: silica gel Eluent: dichloromethane with 1.5% methanol Thin-layer chromatography: ~ilica gel plateq .
Mobile phase: dichloromethane/mathanol 90:10 Migration distance: 10 cm Visualization method: I2 vapor The following were obtaLned:
cis-4-{4-[3-(4-Fluorophenoxy)propyl]piperazinyl}l-phenyl-cyclohexanecarbonitrile C26H32FN3O x 2 HCl dihydrochloride, melting point > 250C
Rf - 0.17.
tran~-4-{4-[3-(4-Fluorophenoxy)propyl]piperazinyl}l-phenylcyclohexanecarbonitrile C26~32FN30 x 2 ~Cl dihydrochloride, melting point ~ 250C, Rf - 0.23 ~methylene chloride/methanol] 9:1, silica gel [9iC] .
Proce~s b.
EXAMPL~ 21 cis-4-{4-t2-(4-Chlorophenoxy)ethyl]piperazinyl}1-phenyl-cyclohexanecarbonitrile 5.4 g ~0.02 mol~ of the piperazine from f, 4.7 g (0.02 mol) of 2-(4-chlorophenoxy)ethyl bromlde and 5.5 y of calcium carbonate in 100 ml of methyl ethyl ketone were refluxed for 4 h. The salt~ were removed ancl then "' ~ . '' ~ ' .' ' :
.
. .
.. . .
,-, 2 Q ~ a - 12 - O.Z. 0050/42305 the filtrate was evaporated, the re~idue was taken up in dichloromethane, and the solution wa.~ wa~hed with water, dried and evaporated under reduced pres3ure. The ~ub-stance wa9 di~solved in isopropanol and converted into the hydrochloride by addition of i~opropanolic hydro-chloric acid.
Yield: 60%, C~5H30ClN3O x 2 ~Cl dihydrochloride, melting point > 250C.
The following were obtained in a similar manner:
ci~-4-{4-[2-(4-Fluorophenoxy)ethyl]piperazinyl}l-phenyl-cyclohexanecarbonitrile C25~30FN3O x 2 ~Cl dihydrochloride, mslting point > 260C, Ci 9 - 4-{4-[2-~4-Fluorophenoxy)ethyl]piperazinyl}1-(4-fluorophenyl)cyclohexanecarbonitrile C2,H28F2N3O x 2 HCl dihydrochloride, melting point ~ 260C, cis-4-~4-[(4-Chlorophenoxy)acetyl]piperazxinyl~l-phenyl-cyclohexanecarbonitrile C25H2BClN3O2, melting point 165-170C, BXAMP~E 25 ci~-4-{4-~(N-Phenylcarboxamido)methylJpiperazinyl}-l-phenylcyclohexanecarbonitrile [ 9iC ]
C25~30N4O x 2 ~Cl dihydrochloride, melting point > 300C, EXAMPL~ 26 ci~-4-{4-[(N-(2,6-Dimethylphenyl)carboxamido)methyl]-piperazinyl}-l-phenylcyclohexanecarbonitrile [ 9iC ]
C27E3~N~O x 2 ~Cl dihydrochloride, melting point 295-300C, Ci9-4 - { 4-[3-Phenoxypropyllpiperazinyl}~l-phenylcyclo-hexanecarbonitrile C26~33N3O x 2 ~Cl dihydrochloride, melting point > 250C~
Proce~ 3 C .
EXANoeL~ 28 Ci3-4-{4-[4-Fluorophenoxy]-2-hydroxybutyl]piperaziny}~-.
2 ~
, -! - 13 - O.Z. 0050/42305 1-phenylcyclohexanecarbonitrile 3.7 g (0.0147 mol) of the piperazine prepared as in ~xample A.e) and 2.5 g (0.0147 mcl) of 1,2-epoxy-4~4-fluorophenoxy)butane were di~olved in 70 ml of ethanol and refluxed for 4 h. After the reaction was complete, isopropanolic hydrochloric acid was added to the mixture and the re~ulting hydrochloride wa~
recr-r~tallized from an i~opropanol/water mlxture.
Yield: 70% C2,H34FN302 x 2 HCl dihydrochloride, melting point > 250C.
The following compound~ were obtained in a ~imilar manner ~tarting from the piperazine obtained as in A.e) by reaction with various su~stituted 1,2-epoxy-3-phenoxypropanes:
EXAMPL~ 29 cis-4-{4-~3-Phenoxy-2-hydroxypropyl]piperazinyl}-1-phenylayclohexanecarbonitrile C2~H33N3O2 x 2 HCl dihydrochloride, melting point ~ 250C, EXAMPL~ 30 cis-4-{4-[3-(Phenylmercapto)-2-hydroxypropyl]pipera-zinyl}-l~phenylcyclohexanecarbonitrile C2~H33N3OS x 2 HCl dihydrochloride, melting point > 250C, ~XAMPLE 31 ci~-4-{4-[3-Chlorophenoxy)-2-hydroxy]propyl}piperazinyl}-~5 1-phenylcyclohexanecarbonitrile [~ic~
C2~H32ClN3O2 x 2 ~Cl dihydrochloride, melting point > 250C, ais-4-~4-~3-(2-Cyanophenoxy)-2-hydroxypropyl]pipera-zinyl}-1-phenylcyclohexanecarbonitrile C27H32N~O2 x 2 HCl dihydrochloride, melting point > 250C, Cis-4-{4-[3-(4-Nitrophenoxy)-2-hydroxypropyl]pipera-zinyl}-l-phenylcyclohexanecarbonitrile Ca~3a~4~ x 2 HCl dihydrochloride, melting point > 250C, ~XAMPLE 34 cis-4-{4-[3-~3-Trifluoromethylphenoxy)-2-hydroxypropyl]-piperazinyl}-1-phenylcyclohexanecarbonitrile 209~37~
- - 14 - O.Z. 0050/~2305 C2,~32F3N3O2 x 2 ~Cl dihydrochloride, meltisg point > 250C, ci~-4-{4-~3-(2-Methoxyphenoxy)-2-hydroxypropyl]pipera-zinyl}-1-phenylcyclohexanecarbonitrile C27H35N3O3 x 2 HCl dihydrochloride, melting point > 250C, The following wa~ obtained using 1,2-epoxy-3-phenylpropane:
cis-4-{4-[3-Phenyl-2-hydroxypropyl]piperazinyl}-1-phenyl-cyclohexanecarbonitrile C26~33N3O x 2 ~Cl dihydrochloride, melting point > 250C, The following was obtained in a ~Lmilar manner by reacting the piperazine ~rom Example e) with.p~chloro-~tyrene oxide:
EXAMPL~ 37 cis-4-{4-[2-(4-Chlorophenyl)-2-hydroxyethyl]piperazinyl}-1-phenylcyclohexanecarbonitrile C2~H3~ClN3O x 2 HCl dihydrochloride, melting point ~ 250C, cis-4-{4-~2-(4-Fluorophenyl)-2-hydroxyethyl]piperazinyl}-1-phenylcyclohexanecarbonitrile C2sH30FN3O x 2 HCl dihydrochloride, melting point > 300C, cis-4-{4-t3,3-Dimethyl-3-phenyl-2-hydroxypropyl]pipera-zinyl}-1-phenylcyclohexanecarbonitrile C2~37N3O x 2 ~Cl dihydrochloride, melting point > 300C, ci~ 4-{4-t3-(4-Chlorophenoxy)-2-t-butyl-2-hydroxypropyl]-piperazinyl}-l-phenylcyclohexanecarbonitrile C30~40ClN3Oz x 2 HCl dihydrochloride, melting point > 285-290C, EXAMP~E 41 cis-4-{4-[3-Phenoxy-2-hydroxy-2-methyl]piperazinyl}-1-phenylcyclohexanec~rbonitrile [~ic]
C27~35N3Oz x 2 ~Cl dihydrochlorite, melting point ~ 270C~
ais-4~{4-t3-(2,4-Dichlorophenoxy-2-hydroxy 2-methylpro-'' ~Oa9~
- 15 - O.Z. 0050/42305 pyl]piperazinyl}-1-phenylcyclohexanecarbonitrile C27~33C12N3O2 x 2 ~Cl dihydrochloride, melting point >
270C, EX~NPLE 43 ci~-4-{4-~3-(4-Acetylphenoxy)-2-hydroxypropyl~pipera-zinyl}-l-phenylcyclohexanecarbonitrile C2aH35N~O3 x 2 HCl dihydrochloride, melting point > 280C, EXAMP~E 44 cis-4-{4-[3-(2-Carbomethoxy~-phenoxy-2-hydroxypropyl]pi-porazinyl}-l-phenylcyclohexanecarbonitrile [ 8ic ]
C28~35N3O4 x 2 ~C1 dihydrochloride, melting point 250-260C.
Reaction of the cis/trans mixture., obtained a~ in A.d), of the piperazine with (f)-1,2-epoxy-3-.t4-fluoro-phenoxy)propane as in Example 28 resulted in cis~trans i~omers which were separated by preparative column chromatography as described in Example 18.
The following were isolated:
EXAMP~E 45 (-)tran~-4-{4-~3-(4-Fluorophenoxy)-(S)-2-hydroxypro-pyl]piperazinyl}-1-phenylcyclohexanecarbonitrile C2~H32FN3O2 x 2 HC1 dihydrochloride, meltinq point > 250C, ~a]2539 ~ ~sic] - -12.1 (C - 10 mg/ml, methanol g5%) Rf = 0.4 EX~PI;f~ 4 6 (-)cis-4-{4-t3-(4-Fluorophenoxy)-(S)-2-hydroxypropyl]pi-perazinyl}-l-phenylcyclohexanecarbonitrile aj C2~H~2FN3O2 x 2 HC1 dihydrochloride, melting point > 250C, b) e2~32FN302 x 2 CH3S03~ bi~methanesul~onate, melting point > 250C, c) C2~H32FN3O2 base, melting point > 250C, [a]25~ sic] - -10.1 (C 3 10 mg/ml, methanol 95%) Rf - 0.3 The following were obtained by similar reaction with (-)-1,2-epoxy-3-(4-fluorophenoxy)propane ~ollowed by chromatography:
2 ~
- 16 - O.Z. 0050/~2305 EXAMPL~ 47 (~)-trans-4-{4-[3-(4-Fluorophenoxy)-(R)-2-hydroxypropyl3 piperaziny}-1-phenylcyclohexanecarbonitrile ~9iC]
C2~H37FN302 x 2 HC1 dihydrochloride, melting point > 250C, [a]2589 ~ [~iC] = 11.1 ~C = 10 mg/ml, methanol 95%) - Rf = 0.4 EXAMP~E 48 ~+)-cis-4-{4-[3-(4-Fluorophenoxy)-(R)-2-hydroxypropyl~pi-peraziny}-1-phenylcyclohexanecarbonitrile ~ic]
C26H32FN3O2 x 2 HCl dihydrochloride, melting point ~ 250C
C2~H3ZFN3o2 base, melting point 143-149C
[a]25a9 ~ [sic] = 9.6 ~C ~ 10 mg/ml, methanol 95%) When the reaction was carried out .with pure trans-pipera~ine from Example A.e) and (+)- or lS (-)-1,2-epoxy-3-(4-fluorophenoxy)propane, the sub~tance~
of Examples 46 and 48 were obtained in a yield of 70~.
EXAMP~E ~9 cis-(-)-4-{4-~3-(4-Fluorophenoxy)-2-acetoxypropyl]pipera-ziny}-1-phenylcyclohexanecarbonitrile ~ic]
3 g of the ba~e from Example 29 were re1uxed with 30 ml of acetic anhydride for 1.5 h and then the excess acetic anhydride was removed by distillation under reduced pre~sure. The residue wa~ diasolved in diisoprop-yl ether, and the sub~tance was obtained as the dihydro chloride with ethereal hydrochlorlc acid.
C28~3~FN302 x 2 ~Cl dihydrocloride, melting point 272-275C
cis~ 4-{4-~3-(4-Fluorophenoxy)-2-methoxypropyl]pipera-zinyl}-l-phenylcyclohexanecarbonitrile 4.4 g (0.01 mol) of the base from Example 29 were stirred with 0~3 g of 80~ ~odium hydride 50 ml in DMF and 1.4 g (0.01 mol) of methyl iodide at 25-40C for 12 h.
After the reaction was complete, the mixture wa9 diluted with 250 ml of water, the base was extracted with methylene chloride, the solution was dried, the ~olvent wa~ removed by di~tillation, and the residue was converted with isopropanolic hydrochloric acid into the , ' 2~99~7~
' - 17 - O.Z. 0050/42305 dihydrochloride:
C2,~3~FN302 x 2 HCl dihydrochloride, melting poi~t 270-280C
The dosage depends on the age, condition and weight of the patient and on the mode of administration.
As a rule, the daily do~e of active substance i3 from about 0.1 to 20 mg/kg of body weight on oral admini~tr-ation and from about 0.01 to 2 mg/kg of body weight on parenteral administration. Satisfactory re~ult~ are normally achieved with daily oral do~es of from 10 to 100 mg and parenteral dose~ of from 1 to 10 mg.
The novel compounds can be admini~tered in the conventional -~olid or liquid pharmaceutical forms, eg.
uncoated or (film-)coated tablet~, capsules, powders, granules, suppositorie~, solution~, ointments, creams, sprays or transdermal therapeutic sy~tem~. The~e are prepared in a conventional manner in which the active substances can be proces~ed with the conventional pharma-ceutical auxiliaries such as tablet binders, filler~, preservatives, tablet disintegrants, flow regulators antioxidants and/or propellant gases (cf. H. Sucker et al., Pharmazeutische Technologie, ~hieme-Verlag, Stuttgart, 1978). The pharmaceutical forms obtained in thi~ way normally contain ~rom 1 to 75~ by weight of the active substance.
EXAMPLES
A. Preparation of the starting compounds a) 4-(4-benzylpiperazinyl)1-phenylcyclohexanecar-bonitrile 35.0 g of 4-cyano-4-phenylcyclohexanone (0.176 mol), tprepared a~ di~clo~ed in J. Amer.
Chem. Soc. 74, (1972~ 773) were dissolved with 31 g of l-benzylpiperazine (0.176 mol) and 21 g of acetic acid i~ 200 ml of ethanol and, at room temperature, a solution of 12.5 g of sodium cyano-borohydride ~0.19 mol) was slowly added dropwise.
,: , .: ' . ' -- - 2 Q 9~ ~ ~ O o. z . OOS0/42305 The mixture wa~ stirred ov~rnight, and then water was added and the mixture was extracted with dichloromethane. Drying and r~moval of the solvent by distillation resulted in a residue of 46.6 g (76%) of oil.
The dihydrochloride wa~ obtained by treat-ment with hydrochloric acid in isopropanol, C24H29N3 x 2 ~Cl, melting point c 3004C.
Thin-layer chromatography and NMR of thi~
product showed that it was composed of roughly equal amounts of the cis and trans isomers.
b) cis-4-(4-benzylpiperazinyl~l-phenylcyclohexane-carb~nitrile The isomer mixture from a) was dis~olved in ethyl acetate, and hexane was added to opalescence.
The pure cia compound crystallized out overnight.
Filtration with suction resulted in 15.5 g (33~).C24H~9N3, melting point 120-123~C.
c) cis-4-~4-benzylpiperazinyl)1-phenylcyclo-hexanecarbonitrile 5 g o~ 4-cyano-4-phenylcyclohexanone (0.025 mol) were heated with 4.4 g (0.025 mol) of l-benzylpiperazine to 100C and then 1.5 ml of formlc acid were qlowly added dropwise while stirring, and the mixture was stirred at 100C for a further 3 h. After cooling, 10 ml of ethyl acetate/hexane mixture were added: after leaving to stand overnight, 5.0 g (55%) of pure compound were obtained. C2~2aN3, melting point 120-123C.
d) 4-piperazinyl-1-phenylcyclohexanecarbonitrile 12.7 g (0.035 mol) of the product prepared as in a) were hydrogenated with 1 g of 10% Pd on carbon catalyst and hydrogen in methanolic hydro-chloric acid ~olution under atmo~pheric pressure.
After hydrogen uptake ceased, the catalyst wa~
filtered off and the ~olution was evaporated. After treatment with alkali and extraction with ether, .
.
~ ~ . , ' ,' ' , :, :. ~ . ,; .~. . .. ..
~ s~ a o.æ. 0050/42305 the above base was i301ated a~ ci~/tran~ i~omer mixture.
Cl7~23N3, yield 95%, C17H23N3 x 2 HCl dihydrochloride, melting point > 330C
e) cis-4-piperazinyl-1-phenylcyclohexanecarbonitrile The compound wa~ obtained from the product obtained as in b) by hydrogenation in a simllar manner to d). Yield Cl,H23N~, melting point 109-113C
~) Preparation of the compounds according to the inven-}0 tion Proce~s a.
cis-(4-Cinnamyl)piperazinyl-l-phenylcyclo-hexanecarbonitrile 6.0 g ~0.03 mol of 4-cyano-4-phenylcyclohexanone were heated with 6.1 g ~0.03 mol~ o~ cinnamylpiperazine to 100C and then 1.5 g (0.033 mol) o~ ~ormic acid were ~lowly added dropwise, while ~tirring, and the mixture wa~ ~tirred at 100C for a further 3 h.
It was the~ diluted with ethyl acetate and wa~hed with 2 N sodium hydroxide ~olution. The organic phaYe was dried and evaporated. The re~idue was taken up in i~opropanol and the hydrochloride was obtained by addition of i~opropa~olic hydrochloric acid. Yield: 50%
C25~31N3 x 2 ~Cl dihydrochloride, melting point > 250C
The following were prepared in a ~imilar manner:
cis-4-~4-~3-(4-Fluorophenoxy) 2-hydroxypropyl]pipera zinyl}l-(4-fluorophenyl)cyclohexanecarbonitril~
C2~H4lF2N3 x 2 HCl dihydrochlorids, melting point > 250C.
EXAMPL~ 3 ci~-4-{4-~3-(4-Fluorophenoxy~-2-hydroxypropyl]pipera zinyl}l-~2-chlorophe~yl)cyclohexanec~rbonitrile C26~3~ClFN3O2 x 2 ~Cl dihydrochloride, m~lting point > 250C.
.
'`` : .: ' `
209~
_ g _ o.z~ 0050/42305 cis-4-~4-[3-Phenoxy-2 hydroxypropyl]piperazinyl}l-~3-methoxyphenyl)cyclohexanecarbonitrile C27H35N3O3 x 2 HCl dihydrochloride, melti.ng point > 290C.
EXA~PLE 5 cis-4-[4-(3-Phenoxy-2-hydroxypropyl)piperazinyl}1-phenyl-cyclohexanecarbonitrile C26H33N3O2 x 2 HCl dihydrochloride, melti.ng point ~ 250C.
ci~-4-{4-[3-(4-Fluorophenoxy)-2-hydroxypropyl]pipera-zinyl}1-(2-pyridyl)cyclohexanecarbonitrile C2sH3lFN402 x 2 HCl dihydrochloride, melting point 274-278C.
EXAMPL~ 7 ciY-4-{4-[2-(4-Fluorophenoxy)ethyl]piperazinyl~1-(2-pyridyl)cyclohexanecarbonitrile C24H29FN40 x 2 HCl dihydrochloride, me~ting point 282-287C.
E%AMPLE 8 cis-4-{4-[3-(4-Fluorophenoxy)-2-hydroxypropyl]pipera-zinyl}l-(2-thienyl)cyclohexanecarbonitrile Cz4H30FN3O2S x 2 HC1 dihydrochloride, melting point > 250C.
ci~-4-{4-~2-(4-Fluorophenoxy)ethyl]piperazinyl}1-(4-chlorophenyl)cyclohexanecarbonitrile C25~29ClFN30 x 2 HC1 dihydrochloride, melting point 2io-2800c.
cis-4-{4-~3-(4-Fluorophenoxy)-2-hydroxypropyl~pipera-zinyl}l-(3-methoxyphenyl)cyclohexanecarbonitrile C27H34FN3O3 x 2 HC1 dihydrochloride, melting point 29~-300C.
EXAMPL~ 11 cis-4-~4-t3-~4-Fluorophenoxy)-2-hydroxypropyl]pipera-zinyl}l-(3-chlorophenyl)cyclohexanecarbonitrile C26H3~ClFN3O2 x ~ HCl dihydrochloride, melting point 250C.
: .
' . ~
, ~- 2Q~S3~
- 10 - O.Z. 0050/42305 cis-4-{4-~3-(4-Fluorophenoxy~-2-hydroxypropyl]pipera-zinyl}l-(4-methoxyphenyl)cyclohexanecarbonitrile C2,H34FN3O3 x 2 HCl dihydroc~loride, melting point ~ 280C
ci~-4-{4-[3-(4-Fluorophenoxy)-2-hydroxypropyl]pipera-zinyl}l-(2-methoxyphenyl)cyclohexanecarbonitrile C27H34FN3O3 x 2 HCl dihydrochloride, melting point ~ 250C.
EXAMPL~ 14 cis-4-{4-[3-(4 F}uorophenoxy)-2-hydroxypropyl]piper-azinyl}l-(4-hydroxyphenyl)cyclohexanecarbonitrile C28~32FN303 x 2 HCl dihydrochloride, melting point > 250C.
EXA~PLE 15 4-t4-(3-Phenoxypropyl]piperazinyl-l-phenylcyclohexane-carbonitrile [ 9iC ]
5-0 g (0-025 mol) of 4-cyano-4-phenylcyclohexa-none and 5.5 g ~0.025 mol) of 3-phenoxypropylpiperazine were dis~olved with 3.0 g o acetic acid in 70 ml of ethanol and then, while stirring at room temperature, a solution of 1.7 g (0.027 mol) of sodium cyanoborohydride was slowly added dropwise. The mixture was stirred ovsrnight and then diluted with water and extracted with dichloromethane. The organic pha3e was ~ubsequently washed wi~h dilute acid (p~ 4), dilute qodium hydroxide solution and water and finally dried and evaporated. The residue was converted into the hydrochloride with i90-propanolic hydrochloric acid, and the product was recry~talllzed from isopropanol/watsr.
Yield: 50%, Cz~33NsO x 2 ~Cl dihydrochloride, melting point > 250C
The following compound~ were prepared in a sLmilar manner:
EXAMPL~ 16 4~{4-t3-(4-Fluorophenoxy)-2-hydroxypropyl]piperazlnyl}-1-t2-methylphenyl)cyclohexanecarbonitrile C27H34FN3Oz x 2 HCl dihydrochloride, melting point ~ 250C.
2~9~7~
U. Z . 0050/~1s2305 4-{4-~2-(4-Chlorothiophenoxy)ethyl]piperazinyl~1-phenyl-cyclohexanecar~onitrile [~ic]
C25H30ClN3S x 2 ~Cl dihydrochloride, melting point > 270C.
4-~4-[3-(4-Fluorophenoxy)propyl]piperazinyl}l-phenyl-cyclohexanecarbonitrile C26H32FN30 x 2 HCl dihydrochloride, melting point > 250C.
The cis/trans i~omer~ of the compound were separated by preparative column chromatography.
Sorbent: silica gel Eluent: dichloromethane with 1.5% methanol Thin-layer chromatography: ~ilica gel plateq .
Mobile phase: dichloromethane/mathanol 90:10 Migration distance: 10 cm Visualization method: I2 vapor The following were obtaLned:
cis-4-{4-[3-(4-Fluorophenoxy)propyl]piperazinyl}l-phenyl-cyclohexanecarbonitrile C26H32FN3O x 2 HCl dihydrochloride, melting point > 250C
Rf - 0.17.
tran~-4-{4-[3-(4-Fluorophenoxy)propyl]piperazinyl}l-phenylcyclohexanecarbonitrile C26~32FN30 x 2 ~Cl dihydrochloride, melting point ~ 250C, Rf - 0.23 ~methylene chloride/methanol] 9:1, silica gel [9iC] .
Proce~s b.
EXAMPL~ 21 cis-4-{4-t2-(4-Chlorophenoxy)ethyl]piperazinyl}1-phenyl-cyclohexanecarbonitrile 5.4 g ~0.02 mol~ of the piperazine from f, 4.7 g (0.02 mol) of 2-(4-chlorophenoxy)ethyl bromlde and 5.5 y of calcium carbonate in 100 ml of methyl ethyl ketone were refluxed for 4 h. The salt~ were removed ancl then "' ~ . '' ~ ' .' ' :
.
. .
.. . .
,-, 2 Q ~ a - 12 - O.Z. 0050/42305 the filtrate was evaporated, the re~idue was taken up in dichloromethane, and the solution wa.~ wa~hed with water, dried and evaporated under reduced pres3ure. The ~ub-stance wa9 di~solved in isopropanol and converted into the hydrochloride by addition of i~opropanolic hydro-chloric acid.
Yield: 60%, C~5H30ClN3O x 2 ~Cl dihydrochloride, melting point > 250C.
The following were obtained in a similar manner:
ci~-4-{4-[2-(4-Fluorophenoxy)ethyl]piperazinyl}l-phenyl-cyclohexanecarbonitrile C25~30FN3O x 2 ~Cl dihydrochloride, mslting point > 260C, Ci 9 - 4-{4-[2-~4-Fluorophenoxy)ethyl]piperazinyl}1-(4-fluorophenyl)cyclohexanecarbonitrile C2,H28F2N3O x 2 HCl dihydrochloride, melting point ~ 260C, cis-4-~4-[(4-Chlorophenoxy)acetyl]piperazxinyl~l-phenyl-cyclohexanecarbonitrile C25H2BClN3O2, melting point 165-170C, BXAMP~E 25 ci~-4-{4-~(N-Phenylcarboxamido)methylJpiperazinyl}-l-phenylcyclohexanecarbonitrile [ 9iC ]
C25~30N4O x 2 ~Cl dihydrochloride, melting point > 300C, EXAMPL~ 26 ci~-4-{4-[(N-(2,6-Dimethylphenyl)carboxamido)methyl]-piperazinyl}-l-phenylcyclohexanecarbonitrile [ 9iC ]
C27E3~N~O x 2 ~Cl dihydrochloride, melting point 295-300C, Ci9-4 - { 4-[3-Phenoxypropyllpiperazinyl}~l-phenylcyclo-hexanecarbonitrile C26~33N3O x 2 ~Cl dihydrochloride, melting point > 250C~
Proce~ 3 C .
EXANoeL~ 28 Ci3-4-{4-[4-Fluorophenoxy]-2-hydroxybutyl]piperaziny}~-.
2 ~
, -! - 13 - O.Z. 0050/42305 1-phenylcyclohexanecarbonitrile 3.7 g (0.0147 mol) of the piperazine prepared as in ~xample A.e) and 2.5 g (0.0147 mcl) of 1,2-epoxy-4~4-fluorophenoxy)butane were di~olved in 70 ml of ethanol and refluxed for 4 h. After the reaction was complete, isopropanolic hydrochloric acid was added to the mixture and the re~ulting hydrochloride wa~
recr-r~tallized from an i~opropanol/water mlxture.
Yield: 70% C2,H34FN302 x 2 HCl dihydrochloride, melting point > 250C.
The following compound~ were obtained in a ~imilar manner ~tarting from the piperazine obtained as in A.e) by reaction with various su~stituted 1,2-epoxy-3-phenoxypropanes:
EXAMPL~ 29 cis-4-{4-~3-Phenoxy-2-hydroxypropyl]piperazinyl}-1-phenylayclohexanecarbonitrile C2~H33N3O2 x 2 HCl dihydrochloride, melting point ~ 250C, EXAMPL~ 30 cis-4-{4-[3-(Phenylmercapto)-2-hydroxypropyl]pipera-zinyl}-l~phenylcyclohexanecarbonitrile C2~H33N3OS x 2 HCl dihydrochloride, melting point > 250C, ~XAMPLE 31 ci~-4-{4-[3-Chlorophenoxy)-2-hydroxy]propyl}piperazinyl}-~5 1-phenylcyclohexanecarbonitrile [~ic~
C2~H32ClN3O2 x 2 ~Cl dihydrochloride, melting point > 250C, ais-4-~4-~3-(2-Cyanophenoxy)-2-hydroxypropyl]pipera-zinyl}-1-phenylcyclohexanecarbonitrile C27H32N~O2 x 2 HCl dihydrochloride, melting point > 250C, Cis-4-{4-[3-(4-Nitrophenoxy)-2-hydroxypropyl]pipera-zinyl}-l-phenylcyclohexanecarbonitrile Ca~3a~4~ x 2 HCl dihydrochloride, melting point > 250C, ~XAMPLE 34 cis-4-{4-[3-~3-Trifluoromethylphenoxy)-2-hydroxypropyl]-piperazinyl}-1-phenylcyclohexanecarbonitrile 209~37~
- - 14 - O.Z. 0050/~2305 C2,~32F3N3O2 x 2 ~Cl dihydrochloride, meltisg point > 250C, ci~-4-{4-~3-(2-Methoxyphenoxy)-2-hydroxypropyl]pipera-zinyl}-1-phenylcyclohexanecarbonitrile C27H35N3O3 x 2 HCl dihydrochloride, melting point > 250C, The following wa~ obtained using 1,2-epoxy-3-phenylpropane:
cis-4-{4-[3-Phenyl-2-hydroxypropyl]piperazinyl}-1-phenyl-cyclohexanecarbonitrile C26~33N3O x 2 ~Cl dihydrochloride, melting point > 250C, The following was obtained in a ~Lmilar manner by reacting the piperazine ~rom Example e) with.p~chloro-~tyrene oxide:
EXAMPL~ 37 cis-4-{4-[2-(4-Chlorophenyl)-2-hydroxyethyl]piperazinyl}-1-phenylcyclohexanecarbonitrile C2~H3~ClN3O x 2 HCl dihydrochloride, melting point ~ 250C, cis-4-{4-~2-(4-Fluorophenyl)-2-hydroxyethyl]piperazinyl}-1-phenylcyclohexanecarbonitrile C2sH30FN3O x 2 HCl dihydrochloride, melting point > 300C, cis-4-{4-t3,3-Dimethyl-3-phenyl-2-hydroxypropyl]pipera-zinyl}-1-phenylcyclohexanecarbonitrile C2~37N3O x 2 ~Cl dihydrochloride, melting point > 300C, ci~ 4-{4-t3-(4-Chlorophenoxy)-2-t-butyl-2-hydroxypropyl]-piperazinyl}-l-phenylcyclohexanecarbonitrile C30~40ClN3Oz x 2 HCl dihydrochloride, melting point > 285-290C, EXAMP~E 41 cis-4-{4-[3-Phenoxy-2-hydroxy-2-methyl]piperazinyl}-1-phenylcyclohexanec~rbonitrile [~ic]
C27~35N3Oz x 2 ~Cl dihydrochlorite, melting point ~ 270C~
ais-4~{4-t3-(2,4-Dichlorophenoxy-2-hydroxy 2-methylpro-'' ~Oa9~
- 15 - O.Z. 0050/42305 pyl]piperazinyl}-1-phenylcyclohexanecarbonitrile C27~33C12N3O2 x 2 ~Cl dihydrochloride, melting point >
270C, EX~NPLE 43 ci~-4-{4-~3-(4-Acetylphenoxy)-2-hydroxypropyl~pipera-zinyl}-l-phenylcyclohexanecarbonitrile C2aH35N~O3 x 2 HCl dihydrochloride, melting point > 280C, EXAMP~E 44 cis-4-{4-[3-(2-Carbomethoxy~-phenoxy-2-hydroxypropyl]pi-porazinyl}-l-phenylcyclohexanecarbonitrile [ 8ic ]
C28~35N3O4 x 2 ~C1 dihydrochloride, melting point 250-260C.
Reaction of the cis/trans mixture., obtained a~ in A.d), of the piperazine with (f)-1,2-epoxy-3-.t4-fluoro-phenoxy)propane as in Example 28 resulted in cis~trans i~omers which were separated by preparative column chromatography as described in Example 18.
The following were isolated:
EXAMP~E 45 (-)tran~-4-{4-~3-(4-Fluorophenoxy)-(S)-2-hydroxypro-pyl]piperazinyl}-1-phenylcyclohexanecarbonitrile C2~H32FN3O2 x 2 HC1 dihydrochloride, meltinq point > 250C, ~a]2539 ~ ~sic] - -12.1 (C - 10 mg/ml, methanol g5%) Rf = 0.4 EX~PI;f~ 4 6 (-)cis-4-{4-t3-(4-Fluorophenoxy)-(S)-2-hydroxypropyl]pi-perazinyl}-l-phenylcyclohexanecarbonitrile aj C2~H~2FN3O2 x 2 HC1 dihydrochloride, melting point > 250C, b) e2~32FN302 x 2 CH3S03~ bi~methanesul~onate, melting point > 250C, c) C2~H32FN3O2 base, melting point > 250C, [a]25~ sic] - -10.1 (C 3 10 mg/ml, methanol 95%) Rf - 0.3 The following were obtained by similar reaction with (-)-1,2-epoxy-3-(4-fluorophenoxy)propane ~ollowed by chromatography:
2 ~
- 16 - O.Z. 0050/~2305 EXAMPL~ 47 (~)-trans-4-{4-[3-(4-Fluorophenoxy)-(R)-2-hydroxypropyl3 piperaziny}-1-phenylcyclohexanecarbonitrile ~9iC]
C2~H37FN302 x 2 HC1 dihydrochloride, melting point > 250C, [a]2589 ~ [~iC] = 11.1 ~C = 10 mg/ml, methanol 95%) - Rf = 0.4 EXAMP~E 48 ~+)-cis-4-{4-[3-(4-Fluorophenoxy)-(R)-2-hydroxypropyl~pi-peraziny}-1-phenylcyclohexanecarbonitrile ~ic]
C26H32FN3O2 x 2 HCl dihydrochloride, melting point ~ 250C
C2~H3ZFN3o2 base, melting point 143-149C
[a]25a9 ~ [sic] = 9.6 ~C ~ 10 mg/ml, methanol 95%) When the reaction was carried out .with pure trans-pipera~ine from Example A.e) and (+)- or lS (-)-1,2-epoxy-3-(4-fluorophenoxy)propane, the sub~tance~
of Examples 46 and 48 were obtained in a yield of 70~.
EXAMP~E ~9 cis-(-)-4-{4-~3-(4-Fluorophenoxy)-2-acetoxypropyl]pipera-ziny}-1-phenylcyclohexanecarbonitrile ~ic]
3 g of the ba~e from Example 29 were re1uxed with 30 ml of acetic anhydride for 1.5 h and then the excess acetic anhydride was removed by distillation under reduced pre~sure. The residue wa~ diasolved in diisoprop-yl ether, and the sub~tance was obtained as the dihydro chloride with ethereal hydrochlorlc acid.
C28~3~FN302 x 2 ~Cl dihydrocloride, melting point 272-275C
cis~ 4-{4-~3-(4-Fluorophenoxy)-2-methoxypropyl]pipera-zinyl}-l-phenylcyclohexanecarbonitrile 4.4 g (0.01 mol) of the base from Example 29 were stirred with 0~3 g of 80~ ~odium hydride 50 ml in DMF and 1.4 g (0.01 mol) of methyl iodide at 25-40C for 12 h.
After the reaction was complete, the mixture wa9 diluted with 250 ml of water, the base was extracted with methylene chloride, the solution was dried, the ~olvent wa~ removed by di~tillation, and the residue was converted with isopropanolic hydrochloric acid into the , ' 2~99~7~
' - 17 - O.Z. 0050/42305 dihydrochloride:
C2,~3~FN302 x 2 HCl dihydrochloride, melting poi~t 270-280C
Claims (5)
1. A 1-aryl-4-piperazinylcyclohexanecarbonitrile of the formula I
I
where Ar is phenyl which is unsubstituted or monosubstituted by chlorine, methyl, methoxy or trifluoromethyl or mono- or disubstituted by fluorine, or is 2- or 3-thienyl or 2-, 3- or 4-pyridyl, R1 is hydrogen, fluorine, chlorine, trifluoromethyl, methoxy, methyl, nitro, cyano, acetyl, methoxycar-bonyl or ethoxycarbonyl, R2 is hydrogen, chlorine or methyl, P is straight-chain or branched alkylene of from 2 to 8 carbons, which can be monosubstituted by oxo, hydroxyl, methoxy or acetoxy, and Q is oxygen or sulfur, NH or a bond, and the salts thereof with physiologically tolerated acids.
I
where Ar is phenyl which is unsubstituted or monosubstituted by chlorine, methyl, methoxy or trifluoromethyl or mono- or disubstituted by fluorine, or is 2- or 3-thienyl or 2-, 3- or 4-pyridyl, R1 is hydrogen, fluorine, chlorine, trifluoromethyl, methoxy, methyl, nitro, cyano, acetyl, methoxycar-bonyl or ethoxycarbonyl, R2 is hydrogen, chlorine or methyl, P is straight-chain or branched alkylene of from 2 to 8 carbons, which can be monosubstituted by oxo, hydroxyl, methoxy or acetoxy, and Q is oxygen or sulfur, NH or a bond, and the salts thereof with physiologically tolerated acids.
2. (-)-cis-4-{4-[3-(4-Fluorophenoxy)-(S)-2-hydroxy-propyl]piperazinyl}-1-phenylcyclohexanecarbonitrile
3. (-)-trans-4-{4-[3-(4-Fluorophenoxy)-(S)-2-hy-droxypropyl]piperazinyl)-1-phenylcyclohexanecarbonitrile
4. A 1-ary1-4-piperazinylcyclohexanecarbonitrile of the formula I as claimed in claim 1 for use in controll-ing diseases.
5. A process for preparing a 1-aryl-4-piperazinyl-cyclohexanecarbonitrile of the formula I
I
where Ar is phenyl which is unsubstituted or monosubstituted by chlorine, methyl, methoxy or trifluoromethyl or mono- or disubstituted by fluorine, or is 2- or 3-thienyl or 2-, 3- or 4-pyridyl, R1 is hydrogen, fluorine, chlorine, methoxy, trifluoro-methyl, methyl, nitro, cyano, acetyl, methoxycar-bonyl or ethoxycarbonyl, R2 is hydrogen, chlorine or methyl, P is straight-chain or branched alkylene of from 2 to 8 carbons, which can be monosubstituted by hydroxyl, methoxy or acetoxy, and Q is oxygen or sulfur, NH or a bond, and the salts thereof with physiologically tolerated acids, which comprises either a) reacting a compound of the formula II
II
where Ar has the stated meanings, with a piperazine derivative III
III
where P, Q, R1 and R2 have the stated meanings, or b) reacting a compound of the formula IV
IV
where Ar has the abovementioned meanings, with a compound of the formula V
V
where P, R1 and R2 [sic] have the abovementioned meanings, and X is a reactive acid residue, or c) if P is monosubstituted by hydroxyl,and Q is not NH, reacting a compound of the formula IV with a compound of the formula VI
VI
where Q, R1 and R2 have the abovementioned meanings, R3 is C1-4-alkyl, and n is 1 or 2, and subsequently converting the resulting compounds where appropriate with physiologically tolerated acids into their salts.
I
where Ar is phenyl which is unsubstituted or monosubstituted by chlorine, methyl, methoxy or trifluoromethyl or mono- or disubstituted by fluorine, or is 2- or 3-thienyl or 2-, 3- or 4-pyridyl, R1 is hydrogen, fluorine, chlorine, methoxy, trifluoro-methyl, methyl, nitro, cyano, acetyl, methoxycar-bonyl or ethoxycarbonyl, R2 is hydrogen, chlorine or methyl, P is straight-chain or branched alkylene of from 2 to 8 carbons, which can be monosubstituted by hydroxyl, methoxy or acetoxy, and Q is oxygen or sulfur, NH or a bond, and the salts thereof with physiologically tolerated acids, which comprises either a) reacting a compound of the formula II
II
where Ar has the stated meanings, with a piperazine derivative III
III
where P, Q, R1 and R2 have the stated meanings, or b) reacting a compound of the formula IV
IV
where Ar has the abovementioned meanings, with a compound of the formula V
V
where P, R1 and R2 [sic] have the abovementioned meanings, and X is a reactive acid residue, or c) if P is monosubstituted by hydroxyl,and Q is not NH, reacting a compound of the formula IV with a compound of the formula VI
VI
where Q, R1 and R2 have the abovementioned meanings, R3 is C1-4-alkyl, and n is 1 or 2, and subsequently converting the resulting compounds where appropriate with physiologically tolerated acids into their salts.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE4108527A DE4108527A1 (en) | 1991-03-15 | 1991-03-15 | NEW 1- (4-CYANO-4-ARYL-CYCLOHEXYL) PIPERAZINE, THEIR PRODUCTION AND USE |
| DEP4108527.2 | 1991-03-15 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2099870A1 true CA2099870A1 (en) | 1992-09-16 |
Family
ID=6427416
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002099870A Abandoned CA2099870A1 (en) | 1991-03-15 | 1992-03-05 | 1-aryl-4-piperazinylcyclohexanecarbonitriles, the preparation and use thereof |
Country Status (15)
| Country | Link |
|---|---|
| US (1) | US5371088A (en) |
| EP (1) | EP0575361B1 (en) |
| JP (1) | JPH06505717A (en) |
| AT (1) | ATE139773T1 (en) |
| AU (1) | AU658173B2 (en) |
| CA (1) | CA2099870A1 (en) |
| CZ (1) | CZ118893A3 (en) |
| DE (2) | DE4108527A1 (en) |
| DK (1) | DK0575361T3 (en) |
| ES (1) | ES2089503T3 (en) |
| FI (1) | FI933883A0 (en) |
| NZ (1) | NZ241962A (en) |
| TW (1) | TW218872B (en) |
| WO (1) | WO1992016516A1 (en) |
| ZA (1) | ZA921866B (en) |
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| US7022402B2 (en) * | 2003-07-14 | 2006-04-04 | E. I. Du Pont De Nemours And Company | Dielectric substrates comprising a polymide core layer and a high temperature fluoropolymer bonding layer, and methods relating thereto |
Family Cites Families (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2722529A (en) * | 1955-11-01 | Amides of certain l-amevoalkyl-x-phenyl | ||
| DE1793383C3 (en) * | 1968-09-10 | 1979-03-01 | Knoll Ag, 6700 Ludwigshafen | 4-Cyano-4-phenyl-aminocyclohexanes and their water-soluble salts, processes for their preparation and pharmaceuticals containing them |
| DE1795362A1 (en) * | 1968-09-19 | 1972-01-05 | Boehringer Mannheim Gmbh | Basic ethers and methods of making them |
| US3773939A (en) * | 1971-11-24 | 1973-11-20 | Janssen Pharmaceutica Nv | N-arallyl-n'-aralkyl piperazine pharmaceutical compositions |
| GB1452413A (en) * | 1973-08-16 | 1976-10-13 | Fuji Chem Ind Co Ltd | |
| IL48309A (en) * | 1974-10-25 | 1980-01-31 | Robins Co Inc A H | 1-aryloxy-4-amino-2-butanols and pharmaceutical compositions containing them |
| US4369184A (en) * | 1980-01-24 | 1983-01-18 | Janssen Pharmaceutica N.V. | 1-(Cyclohexyl)-4-aryl-4-piperidinecarboxylic acid derivatives |
| JPS59101475A (en) * | 1982-12-02 | 1984-06-12 | Nippon Chemiphar Co Ltd | Novel piperazine derivative, its preparation and cerebral circulation improving agent containing the same |
| JPS60222472A (en) * | 1984-03-30 | 1985-11-07 | Kanebo Ltd | Novel piperazine derivative and drug composition containing the same as an active ingredient |
| DE3600390A1 (en) * | 1986-01-09 | 1987-07-16 | Hoechst Ag | DIARYLALKYL-SUBSTITUTED ALKYLAMINE, METHOD FOR THE PRODUCTION THEREOF, THEIR USE AND MEDICINAL PRODUCTS CONTAINING THE SAME |
| JPH08776B2 (en) * | 1986-08-20 | 1996-01-10 | 日本ケミフア株式会社 | Pharmaceutical composition having brain cell protective action |
| DE3643009A1 (en) * | 1986-12-17 | 1988-06-30 | Basf Ag | FUNGICIDAL CYCLOHEXYLAMINE |
| US4880808A (en) * | 1987-04-01 | 1989-11-14 | Janssen Pharmaceutica N.V. | N-aryl-piperazinealkanamides useful for improving sleep |
-
1991
- 1991-03-15 DE DE4108527A patent/DE4108527A1/en not_active Withdrawn
-
1992
- 1992-03-05 JP JP4505495A patent/JPH06505717A/en active Pending
- 1992-03-05 US US08/117,103 patent/US5371088A/en not_active Expired - Fee Related
- 1992-03-05 DE DE59206667T patent/DE59206667D1/en not_active Expired - Fee Related
- 1992-03-05 AT AT92905289T patent/ATE139773T1/en not_active IP Right Cessation
- 1992-03-05 CZ CS931188A patent/CZ118893A3/en unknown
- 1992-03-05 AU AU13601/92A patent/AU658173B2/en not_active Expired - Fee Related
- 1992-03-05 CA CA002099870A patent/CA2099870A1/en not_active Abandoned
- 1992-03-05 ES ES92905289T patent/ES2089503T3/en not_active Expired - Lifetime
- 1992-03-05 DK DK92905289.2T patent/DK0575361T3/en active
- 1992-03-05 EP EP92905289A patent/EP0575361B1/en not_active Expired - Lifetime
- 1992-03-05 WO PCT/EP1992/000488 patent/WO1992016516A1/en active IP Right Grant
- 1992-03-10 TW TW081101814A patent/TW218872B/zh active
- 1992-03-13 ZA ZA921866A patent/ZA921866B/en unknown
- 1992-03-13 NZ NZ241962A patent/NZ241962A/en unknown
-
1993
- 1993-09-06 FI FI933883A patent/FI933883A0/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| FI933883A (en) | 1993-09-06 |
| ZA921866B (en) | 1993-09-13 |
| ES2089503T3 (en) | 1996-10-01 |
| CZ118893A3 (en) | 1994-02-16 |
| TW218872B (en) | 1994-01-11 |
| JPH06505717A (en) | 1994-06-30 |
| DE4108527A1 (en) | 1992-09-17 |
| AU1360192A (en) | 1992-10-21 |
| EP0575361A1 (en) | 1993-12-29 |
| ATE139773T1 (en) | 1996-07-15 |
| DE59206667D1 (en) | 1996-08-01 |
| DK0575361T3 (en) | 1996-07-29 |
| NZ241962A (en) | 1993-05-26 |
| US5371088A (en) | 1994-12-06 |
| AU658173B2 (en) | 1995-04-06 |
| EP0575361B1 (en) | 1996-06-26 |
| WO1992016516A1 (en) | 1992-10-01 |
| FI933883A0 (en) | 1993-09-06 |
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